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【结 构 式】 
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【分子编号】14681 【品名】benzyl N-[(1S,2S,3S,4R)-3-(2-oxoethyl)bicyclo[2.2.1]hept-2-yl]carbamate 【CA登记号】 |
【 分 子 式 】C17H21NO3 【 分 子 量 】287.35868 【元素组成】C 71.06% H 7.37% N 4.87% O 16.7% |
合成路线1
该中间体在本合成路线中的序号：(XXI)The alkylation of bicyclo[2.2.1]heptan-2-one (XV) with allyl bromide and BuLi in THF gives exo-3-allylbicyclo[2.2.1]heptan-2-one (XVI), which by reaction with hydroxylamine is converted into the corresponding oxime (XVII). The reduction of (XVII) with LiAlH4 in THF yields 3exo-allylbicyclo[2.2.1]heptan-2endo-amine (XVIII), which is acylated with benzyloxycarbonylchloride by means of pyridine in dichloromethane to the carbamic ester (XIX). The epoxidation of (XIX) with m-chloroperbenzoic acid in dichloromethane affords the epoxide (XX), which by oxidation with HIO4 is converted into the aldehyde (XXI). The Wittig condensation of (XXI) with 4-carboxybutyl triphenylphosphonium bromide by means of NaH in DMSO, followed by methylation with CH2N2 affords 7-[3endo-(benzyloxycarbonylamino)bicyclo[2.2.1]hept-2exo-yl]-5(Z)-heptenoic acid methyl ester (XXII), which is deprotected with trifluoroacetic acid to the free amino ester (XXIII). The acylation of (XXIII) with benzenesulfonyl chloride as before gives the sulfonamide ester (XXIV), which is finally hydrolyzed with KOH in methanol - water to 7-[3endo-(phenylsulfonamido)bicyclo[2.2.1]hept-2exo-yl]-5(Z)-heptenoic acid (XIV) as a racemic mixture.
| 【1】 Watanabe, F.; Narisada, M.; Ohtani, M.; Hagishita, S.; Tsuri, T.; Seno, K.; Tsushima, T.; Kamata, S.; Kawada, K.; Haga, N. (Shionogi & Co. Ltd.); Bicyclic sulfonamide derivs. EP 0226346; GB 2184118; JP 1988139161; US 5043451; US 5043456 . |
| 【2】 Narisada, M.; Uchida, K.; Otani, K.; Doteuchi, M.; Hanasaki, K.; Ohtani, M.; Hara, S.; Arita, H.; Watanabe, F.; Kakushi, H.; Synthesis and in vitro activity of various derivatives of a novel thromboxane receptor antagonist, (±)-5(Z)-7-[3-endo-[(phenylsulfonyl)aminobicyclo[2.2.1]hept-2-exo-yl] heptenoic acid. J Med Chem 1988, 31, 9, 1847-54. |
| 【3】 Narisada, M.; Ohtani, M.; Watanabe, F.; et al.; Synthesis and in vitro effects on platelet and vascular smooth muscle of S-145, a novel thromboxane receptor antagonist. Advances in Prostaglandin, Thromboxane, and Leukotriene Research, Vol. 19. B. Samuelsson, P.Y.-K. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIV) | 14674 | (Z)-7-[(1R,2S,3S,4S)-3-[(phenylsulfonyl)amino]bicyclo[2.2.1]hept-2-yl]-5-heptenoic acid | C20H27NO4S | 详情 | 详情 | |
| (XV) | 14675 | (1S,4R)bicyclo[2.2.1]heptan-2-one | 2630-41-3 | C7H10O | 详情 | 详情 |
| (XVI) | 14676 | (1S,3S,4R)-3-allylbicyclo[2.2.1]heptan-2-one | C10H14O | 详情 | 详情 | |
| (XVII) | 14677 | (1S,3S,4R)-3-allylbicyclo[2.2.1]heptan-2-one oxime | C10H15NO | 详情 | 详情 | |
| (XVIII) | 14678 | (1S,2S,3S,4R)-3-allylbicyclo[2.2.1]hept-2-ylamine; (1S,2S,3S,4R)-3-allylbicyclo[2.2.1]heptan-2-amine | C10H17N | 详情 | 详情 | |
| (XIX) | 14679 | benzyl N-[(1S,2S,3S,4R)-3-allylbicyclo[2.2.1]hept-2-yl]carbamate | C18H23NO2 | 详情 | 详情 | |
| (XX) | 14680 | benzyl N-[(1S,2S,3S,4R)-3-(2-oxiranylmethyl)bicyclo[2.2.1]hept-2-yl]carbamate | C18H23NO3 | 详情 | 详情 | |
| (XXI) | 14681 | benzyl N-[(1S,2S,3S,4R)-3-(2-oxoethyl)bicyclo[2.2.1]hept-2-yl]carbamate | C17H21NO3 | 详情 | 详情 | |
| (XXII) | 14682 | methyl (Z)-7-((1R,2S,3S,4S)-3-[[(benzyloxy)carbonyl]amino]bicyclo[2.2.1]hept-2-yl)-5-heptenoate | C23H31NO4 | 详情 | 详情 | |
| (XXIII) | 14683 | methyl (Z)-7-[(1R,2S,3S,4S)-3-aminobicyclo[2.2.1]hept-2-yl]-5-heptenoate | C15H25NO2 | 详情 | 详情 | |
| (XXIV) | 14684 | methyl (Z)-7-[(1R,2S,3S,4S)-3-[(phenylsulfonyl)amino]bicyclo[2.2.1]hept-2-yl]-5-heptenoate | C21H29NO4S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IL)The reaction of (1R,2S,3S,4S)-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-monomethyl ester (XLIII) with ethylchloroformate and NaN3 gives the corresponding azide (XLIV), which is submitted to degradation in the presence of benzyl alcohol to afford (1R,2S,3S,4S)-3-(benzyloxycarbonylamino)bicyclo[2.2.1]heptane-2-carboxylic acid methyl ester (XLV). The reduction of (XLV) with NaBH4 in THF gives the hydroxymethyl derivative (XLVI), which is oxidized with oxalyl chloride as before to the corresponding aldehyde (XLVII). The Wittig condensation of (XLVII) with methoxymethyl triphenylphosphonium chloride by means of t-BuOK in THF gives the vinyl ether (XLVIII), which is hydrolyzed to the corresponding aldehyde (XLIX) with formic acid. A new Wittig condensation of (XLIX) with 4-carboxybutyl triphenylphosphonium bromide as before, followed by methylation with diazomethane yields (1R,2S,3S,4S)-7-[3-(benzyloxycarbonylamino)bicyclo[2.2.1]heptan-2-yl]-5(Z)-heptenoic acid methyl ester (L). The deprotection of (L) with trifluoroacetic acid affords the 3-amino derivative (LI), which is then condensed with [14C]- or [3H]-radiolabeled benzenesulfonyl chloride (LII) to afford the radiolabeled sulfonamide ester (LIII). Finally, this compound is hydrolyzed with NaOH to the radiolabeled free acid (XIV), already obtained, which is converted to S-1452 by treatment of the Na salt with CaCl2 in methanol-water.
| 【1】 Narisada, M.; Katsuyama, Y.; Watanabe, F.; Hamada, Y.; Ohtani, M.; Nagasaki, T.; Synthesis of [14C]- and [3H]-labelled (+)-[1R-[1alpha,2alpha(Z),3beta,4alpha]]-7-[3-[(phenylsulfonyl)amino] bicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, ((+)-S-145) and its calcium salt (S-1452). J Label Compd Radiopharm 1992, 31, 1, 23-38. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IL) | 14681 | benzyl N-[(1S,2S,3S,4R)-3-(2-oxoethyl)bicyclo[2.2.1]hept-2-yl]carbamate | C17H21NO3 | 详情 | 详情 | |
| (XIV) | 14674 | (Z)-7-[(1R,2S,3S,4S)-3-[(phenylsulfonyl)amino]bicyclo[2.2.1]hept-2-yl]-5-heptenoic acid | C20H27NO4S | 详情 | 详情 | |
| (XLIII) | 14665 | (1S,2S,3S,4R)-3-(methoxycarbonyl)bicyclo[2.2.1]heptane-2-carboxylic acid | C10H14O4 | 详情 | 详情 | |
| (XLIV) | 14704 | methyl (1R,2S,3S,4S)-3-(azidocarbonyl)bicyclo[2.2.1]heptane-2-carboxylate | C10H13N3O3 | 详情 | 详情 | |
| (XLV) | 14705 | methyl (1R,2S,3S,4S)-3-[[(benzyloxy)carbonyl]amino]bicyclo[2.2.1]heptane-2-carboxylate | C17H21NO4 | 详情 | 详情 | |
| (XLVI) | 14706 | benzyl N-[(1S,2S,3S,4R)-3-(hydroxymethyl)bicyclo[2.2.1]hept-2-yl]carbamate | C16H21NO3 | 详情 | 详情 | |
| (XLVII) | 14707 | benzyl N-[(1S,2S,3S,4R)-3-formylbicyclo[2.2.1]hept-2-yl]carbamate | C16H19NO3 | 详情 | 详情 | |
| (XLVIII) | 14708 | benzyl N-[(1S,2S,3R,4R)-3-[(E)-2-methoxyethenyl]bicyclo[2.2.1]hept-2-yl]carbamate | C18H23NO3 | 详情 | 详情 | |
| (L) | 14682 | methyl (Z)-7-((1R,2S,3S,4S)-3-[[(benzyloxy)carbonyl]amino]bicyclo[2.2.1]hept-2-yl)-5-heptenoate | C23H31NO4 | 详情 | 详情 | |
| (LI) | 14683 | methyl (Z)-7-[(1R,2S,3S,4S)-3-aminobicyclo[2.2.1]hept-2-yl]-5-heptenoate | C15H25NO2 | 详情 | 详情 | |
| (LII) | 14684 | methyl (Z)-7-[(1R,2S,3S,4S)-3-[(phenylsulfonyl)amino]bicyclo[2.2.1]hept-2-yl]-5-heptenoate | C21H29NO4S | 详情 | 详情 | |
| (LIII) | 14713 | benzenesulfonyl chloride | 98-09-9 | C6H5ClO2S | 详情 | 详情 |